Purpose <p>Colorectal cancer (CRC) is identified as the second leading cause of cancer-associated deaths worldwide. Therefore, there is ongoing research to discover new potential biomarkers enabling early and noninvasive diagnosis of the disease. YRNAs, a novel class of non-coding RNAs, have been identified as a new player in carcinogenesis and an independent class of clinical biomarkers in various malignancies. Nevertheless, the role of plasma YRNAs in CRC diagnosis and prognosis remains unknown. Therefore, the current study aimed to investigate the clinical significance of plasma YRNAs as a noninvasive biomarker for CRC.</p> Methods <p>Plasma YRNAs expression was assessed in 50 newly diagnosed CRC patients as well as 50 age- and sex-matched healthy controls using quantitative reverse transcription polymerase chain reaction.</p> Results <p>All plasma YRNAs expression levels were significantly higher in CRC patients than in controls. A significant correlation was observed between YRNA1 and YRNA3, and between YRNA1 and YRNA4. However, no significant correlation between YRNA1 and YRNA5 was identified. Plasma YRNA1 expression showed the highest diagnostic performance for the detection of CRC using the receiver operating characteristic curve analysis, with a sensitivity of 92% and a specificity of 90%. Nevertheless, when the four YRNAs were combined in a single ROC analysis, sensitivity decreased to 80%, while the specificity remained virtually unchanged. Moreover, significant association was observed between plasma YRNA1 and YRNA3 and tumor stage, grade, lymph node presence, metastasis, and lymphovascular invasion.</p> Conclusions <p>Plasma YRNA may serve as a potential noninvasive biomarker for the diagnosis and prognosis of CRC with high sensitivity and specificity vs. healthy controls.</p>